Retinoic acid derivatives are known to have useful pharmacologic and other properties. For example, certain ester and amide derivatives of all-trans retinoic acid are disclosed in U.S. Pat. Nos. 4,190,594 and 4,108,880 as having useful ultraviolet (U.V.) absorption properties. In U.S. Pat. No. 4,055,659, the use of esters and amides of all-trans retinoic acid in the treatment of acne is disclosed. N-(4-hydroxyphenyl)-all-trans-retinamide is disclosed in U.S. Pat. No. 4,323,581 as being useful in the prevention of breast cancer in mammals.
Retinoic acid has been previously reported as the starting material in retinoid synthesis. Common to many synthetic routes in the preparation of retinoids is the conversion of retionic acid to retinoyl chloride by the action of various chlorinating reagents such as thionyl chloride or phosphorus trichloride. A common problem associated with the use of these reagents is the instability of retinoyl chloride and retinoic acid to the chlorinating reagent during the conversion of acid, particularly on a large-scale synthesis. For example, R. C. Moon, et al. have reported in Cancer Research, Vol. 39, page 1339 (1979) that the preparation of retinoyl chloride from retinoic acid by the action of phosphorus trichloride in benzene at room temperature for several hours requires the decantation of the benzene-retinoyl chloride solution from a polymeric by-product. In the Moon procedure, the polymeric by-product is formed, probably as a result of the sensitivity of retionic acid which undergoes facile polymerization. In a similar process reported by Y. F. Shealy et al. in the Journal of Pharmaceutical Sciences, Vol. 73, p. 745 (1984), the product retinoyl chloride must be decanted away from a gummy precipitate which the authors report to be "phosphorus compounds". In either case, the yields of retinoids is diminished as a result of poor yield and quality of retinoyl chloride intermediates. In view of the high cost of the starting material, i.e., retinoic acid, such processes may be disadvantageous. In addition, solutions of retinoyl chloride are prone to rapid light, oxygen, heat, and base-catalyzed decomposition.
In a publication by M. Zaorul and Z. Arnold in Tetrahedron Letters No. 14, pages 9-12 (1960) the authors describe the use of dimethylchloroformamidinium chloride as a reagent in the preparation of certain peptides. H. H. Bosshard, et al. have reported in Helv. Chim. Acta. Vol. 42, page 1653 (1959) the conversion of various carboxylic acids to acid chlorides by the action of a catalytic amount of DMF in the presence of thionyl chloride (which led presumably to the catalyst dimethylchloroformamidinium chloride). However, when the Bosshard conditions are applied to the conversion of all-trans retinoic acid to all-trans retinoyl chloride, decomposition of the retinoic acid is rapid which results in lower yields and impure products.